Colon cancer causes over 60,000 deaths in the United States each year and is second only to lung cancer as the leading cause of cancer deaths in the U.S. Patients who present with premalignant colonic polyps are considered to be at higher risk for developing colon cancer. Patients with an inherited predisposition for developing hundreds of polyps (called familial polyposis) are at nearly 100% risk of colon cancer by age 40. Finally, a large number of colon cancers originate from flat mucosa (i.e., not from a polyp), especially in the proximal colon, so that a prehistory of polyposis which might lead to early detection is lacking. Recently, restriction fragment length polymorphisms (RFLPs) loosely linked to familial polyposis have been described. Elevated ras gene expression is also observed in a large fraction of polyps and carcinomas. In order to directly investigate the major alterations in gene expression in colon carcinoma and in polyps compared to normal colonic mucosa, cDNA libraries from matched tumor/normal tissues were constructed. Subsequently, tumor minus normal and normal minus tumor subtractive cDNA libraries were prepared enriched for tumor-specific and normal-specific cDNAs, respectively. Several cDNA clones whose expression is greatly elevated in carcinoma tissue, but not in normal or polyp tissue, have been isolated. Two of these clones have been identified as keratins, type I and II, which appear to be of a subtype not normally found in colonic mucosa. Other clones have been isolated which are expressed predominantly in normal mucosa. One of these clones has been identified as collagen type VI, a component of the extracellular matrix which may be important in maintaining differentiation in colonic epithelia. Expression of these clones in colon carcinoma cell lines, as well as in other carcinomas (e.g., breast, ovary, lung, kidney) are being examined.